Sphingosine-1-phosphate [(2S,3R,4E)-2-amino-3-hydroxyoctadec-4-enyl-1-phosphate; hereinafter occasionally abbreviated as S1P] is a lipid which is synthesized by metabolic turnover of sphingolipids in cells and by the extracellular action of a secreted sphingosine kinase. It is proposed that sphingosine-1-phosphate acts as an intercellular communication mediator as well as an intracellular second messenger.
Among S1P receptors, with regard to S1P5 (EDG-8) receptor, it is known that S1P5 (EDG-8) receptor is highly expressed in oligodendrocytes (oligodendroglia) and oligodendrocyte progenitor cells (see Non Patent Literatures 1 and 2). Oligodendrocytes are a kind of glial cells which form the myelin sheaths (myelin) by binding to the axons of nerve cells. Accordingly, it is considered that a compound which has an S1P5 receptor binding activity, and can mediate the function of an S1P5 receptor, is useful for treating neurodegenerative disease such as schizophrenia because the compound promotes the regeneration of myelin which has disappeared (demyelination) in nerve cells.
In addition, it is known that S1P5 receptor is highly expressed also in natural killer (NK) cells and it is revealed that the migration of NK cells is induced by the activation of S1P5 receptor (see Non Patent Literature 3).
Further, S1P5 receptor is highly expressed in patrolling monocytes which are known to be involved in the tumor immunity, and therefore, there is a possibility that the activation of the tumor immunity is induced by the activation of S1P5 receptor (see Non Patent Literatures 4 and 5).
Incidentally, as compounds of prior arts to the present invention, the following compounds are known.
It is disclosed that a compound represented by general formula (a):
(wherein, Xa represents CH or N, R1a represents a C3-6 cycloalkyl group which has a fluorine substituent(s), R2a represents a hydrogen atom, a halogen atom, a cyano group or a trifluoromethyl group, Aa represents a 5-membered heterocyclic ring which is chosen between thiazole, thiadiazole or the like, Ba represents bicyclic ring which is chosen between a substituent as shown below;
(wherein, R9a represents a C1-4 alkyl group which has at lease one hydroxy group substituent, R10a represents a hydrogen atom or a C1-3 alkyl group which may be substituted with a halogen atom) (provided that the definition of each of groups is excerpted)) has an S1P1 agonist activity (see Patent Literature 1).
Also, it is known that a compound represented by general formula (b):
(wherein, Xb represents C or N, R1b represents H or an alkyl group which may have a substituent(s), R2b represents H, an alkyl group which may have a substituent(s), a halogen atom or the like, Wb represents C, N or a C-alkoxy group, Qb represents CH2O or the like, Sb represents a substituent as shown below;
(wherein, R3b represents H, an alkyl group, a halogen atom or the like, nb represents 0 to 3) (provided that the definition of each of groups is excerpted)) has an S1P agonist activity (see Patent Literature 2).
None of prior arts discloses or suggests that the compound of the present invention has a selective S1P5 binding activity and modulates the function of an S1P5 receptor.